The present invention relates to vaccination in a subject that has preexistent immunity. While the invention is subject to a wide range of applications, it is especially suited for vaccination in animals and humans against infectious diseases, autoimmune disorders, and cancer.
Preexistent immunity suppresses the efficacy of vaccination against a wide variety of antigens. This phenomenon has been most widely studied in connection with the ability of maternal antibodies to suppress infant responses to vaccination against infectious diseases. Significantly reduced seroconversion rates and/or mean antibody titers in infants immunized in the presence of maternal antibodies were initially reported during vaccination against measles virus more than 25 years ago (Albrecht et al., J. Pediatr. 91:715, 1977). Other live vaccines, including oral polio, varicella-zoster, influenza, and oral human rotavirus vaccines are subject to maternal antibody-mediated immunosuppression (Chan et al., Vaccine 29:1242, 2011; Karron et al., Pediatr. Infect. Dis. J. 14:10, 1995; Perkins et al., Br. Med. J. 1:1083, 1959). Contrary to the initial thought of some skilled in the art, subunit and inactivated vaccines are also inhibited by preexistent antibodies. The efficacy of pertussis vaccine (Burstyn et al., Infect. Immun. 41:1150, 1983; Englund et al., Pediatrics 96:580, 1995), haemophilus influenza type B conjugate vaccines (Claesson et al., J. Pediatr. 114:97, 1989; Daum et al., J. Infect. Dis. 164:1154, 1991), hepatitis A vaccine (Dagan et al., Pediatr. Infect. Dis. J. 19:1045, 2000; Kanra et al., Turk. J. Pediatr. 42:105, 2000; Troisi et al., Vaccine 15:1613, 1997), and tetanus and diphtheria toxoids vaccines (Barr et al., Lancet 1:6, 1950; Bjorkholm et al., Pediatr. Infect. Dis. J. 14:846, 1995; Booy et al., Lancet 339:507, 1992; Sarvas et al., J. Infect. Dis. 165:977, 1992) is reduced in the presence of maternal antibodies. The problem is not limited to the newborn population. Vaccination of individuals of any age with antigens delivered via pathogen-derived vectors (for example, adenovirus-based vaccines) is subject to immunosuppression by preexistent antibodies to that vector (Casimiro et al., J. Virol. 77:6305, 2003; Fitzgerald et al., J. Immunol. 170:1416, 2003). As pathogen-vectored vaccines are currently being developed not only against infectious diseases but also against cancer and autoimmune dysfunction (Hangalapura et al., Vaccine 29:2313, 2011; Spohn et al., J. Immunol. 178:7450, 2007), vaccines against these disorders are also subject to antibody-mediated immunosuppression. Immunosuppression by preexistent antibodies also impacts the veterinary field. Vaccination of livestock, poultry, and horses against debilitating and life-threatening diseases, including pandemic influenza, Newcastle disease virus, and rotavirus is subject to antibody-mediated immunosuppression in the presence of maternal antibodies (Maas et al., Avian. Pathol. 40:87, 2011; Nguyen et al., Clin. Vaccine Immunol. 13:475, 2006; Perozo et al., Avian Dis. 52:253, 2008; Ryan et al., Clin. Vaccine Immunol. 17:1896, 2010; Wesley et al., Vaccine 22:3427, 2004).
Several mechanisms have been proposed to explain the inhibitory effect of maternal antibodies on vaccination. Included among the proposed mechanisms are: neutralization of live viral vaccines rapidly after injection (Albrecht et al., J. Pediatr. 91:715, 1977), epitope masking that prevents antigen binding by naive B cells (Heyman et al., Springer Semin. Immunopathol. 23:421, 2001), elimination of immune complexes by Fc-dependent endocytosis (McKendall et al., J. Infect. Dis. 151:464, 1985; Wallace et al., J. Leukoc. Biol. 55:816, 1994), and colligation of the B cell receptor with FcγRIIB leading to an inhibition of B cell responses (Daeron et al., Annu Rev. Immunol. 15:203, 1997). Some of these theories, such as the epitope-specific masking of B cells, are better supported by available clinical and experimental data than others (Jelonek et al., J. Infect. Dis. 174:866, 1996; Kurikka et al., Pediatr. Infect. Dis. J. 15:530, 1996; Nohynek et al., Pediatr. Infect. Dis. J. 18:25, 1999; Panpitpat et al., Bull. World Health Organ. 78:364, 2000). Additional mechanisms may explain the phenomenon of antibody-mediated immunosuppression.
Counteracting or circumventing the immunosuppressive effect of preexistent immunity on vaccination would greatly benefit public health and agricultural resources. However, efficient methods and vaccine compositions for improving vaccination of subjects with preexistent immunity have not been developed. Cytokine and toll-like receptor-stimulating molecules have been tried in animal models in the context of vaccine formulations targeted to neonates (Arulanandam et al., J. Immunol. 164:3698, 2000; Ishii et al., Gene Ther. 6:237, 1999; Kovarik et al., Arch. Immunol. Ther. Exp. (Warsz) 49:209, 2001; Pertmer et al., Vaccine 19:1764, 2001). DNA- and viral-vectored delivery of vaccine antigens to infants have been proposed but the immunosuppressive effect of maternal antibodies limits the efficacy of these approaches as well (Mahon et al., Curr. Med. Chem. 8:1057, 2001). Based on the epitope-masking theory, it was hypothesized that increasing the dose of vaccine antigen would circumvent inhibition by maternal antibodies as excess antigenic epitopes would remain free of maternal antibodies and become more accessible to infant B cells. Indeed, higher dose hepatitis A vaccine or measles virus vaccine enhanced serological responses in infants vaccinated in the presence of maternal antibodies (Dagan et al., Pediatr. Infect. Dis. J. 19:1045, 2000; Cutts et al., Vaccine 12:1311, 1994). However, excess mortality was seen among infants vaccinated with high doses of live measles vaccine (Knudsen et al., Int. J. Epidemiol. 25:665, 1996). Thus, there remains a need for safe and effective approaches to enhancing the efficacy of vaccination in subjects with preexistent immunity.